Otsuka Pharmaceutical Co., Ltd. has received approval from the Japanese Ministry of Health, Labour and Welfare (MHLW) for NEXLETOL® (bempedoic acid) as a treatment for hypercholesterolemia and familial hypercholesterolemia. The approval marks a significant milestone for both Otsuka and its partner Esperion Therapeutics, establishing the drug's presence across the world's three largest cardiovascular prevention markets.
Novel Mechanism Addresses Unmet Medical Need
NEXLETOL represents an oral, non-statin treatment with a distinctive mechanism of action that inhibits ACLY (adenosine triphosphate citrate lyase), an enzyme upstream of the statin target in the liver's cholesterol synthesis pathway. This ultimately leads to a reduction in blood LDL-cholesterol levels through a different pathway than traditional statin therapy.
The drug addresses a critical gap in cholesterol management for patients who are unable to achieve their target cholesterol levels despite taking statins due to insufficient response, or those who find it difficult to continue statin treatment due to adverse events. NEXLETOL is expected to offer a new therapeutic option for these patients in Japan.
Phase 3 Trial Demonstrates Significant Efficacy
The Japanese approval was supported by a Phase 3 trial (NCT05683340) conducted as a placebo-controlled, randomized, multicenter, double-blind, parallel-group comparative study. The trial enrolled 96 patients with high LDL cholesterol in whom statins had insufficient effect or for whom statin therapy was not suitable.
Trial participants received either 180 mg of NEXLETOL or placebo orally once daily for 12 weeks. The primary endpoint measured the percentage change from baseline in LDL-C at Week 12, which showed a reduction of 25.25% in the NEXLETOL group compared to 3.46% in the placebo group, demonstrating positive outcomes with statistical significance compared to placebo (p<0.001).
The safety profile was favorable, with no serious adverse events observed during the study period, supporting the drug's tolerability in the Japanese patient population.
Global Market Expansion Strategy
"Securing regulatory approval in Japan – one of the top three global markets for cardiovascular prevention – represents a major step forward in our international growth strategy," said Sheldon Koenig, President and CEO of Esperion. "With NEXLETOL now approved across the U.S., Europe, and Japan, we've established a strong global footprint and expanded access to a differentiated, non-statin LDL-C lowering therapy for patients who need alternatives."
Partnership Terms and Financial Implications
Otsuka acquired exclusive development and commercialization rights for NEXLETOL in Japan from Esperion in 2020. Under the collaboration and license agreement, Esperion is eligible to receive significant milestone payments upon regulatory approval and National Health Insurance Price Listing for NEXLETOL in Japan.
The partnership structure also includes additional sales milestone payments based on total net sales achievements by Otsuka in Japan, as well as tiered royalties ranging from fifteen percent to thirty percent on net sales in the Japanese market.
Broader Clinical Development Program
NEXLETOL's development is supported by extensive clinical evidence, including the nearly 14,000 patient CLEAR Cardiovascular Outcomes Trial. Esperion continues to build on its success with its next generation program focused on developing ATP citrate lyase inhibitors (ACLYi), leveraging new insights into the structure and function of ACLYi to enable rational drug design and develop highly potent and specific inhibitors with allosteric mechanisms.
